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Frontiers in Cellular and Infection... 2023Malaria is a parasitic disease of global health significance and a leading cause of death in children living in endemic regions. Although various Plasmodium species are... (Review)
Review
Malaria is a parasitic disease of global health significance and a leading cause of death in children living in endemic regions. Although various Plasmodium species are responsible for the disease, infection accounts for most severe cases of the disease in humans. The mechanisms of cerebral malaria pathogenesis have been studied extensively in humans and animal malaria models; however, it is far from being fully understood. Recent discoveries indicate a potential role of bradykinin and the kallikrein kinin system in the pathogenesis of cerebral malaria. The aim of this review is to highlight how bradykinin is formed in cerebral malaria and how it may impact cerebral blood-brain barrier function. Areas of interest in this context include Plasmodium parasite enzymes that directly generate bradykinin from plasma protein precursors, cytoadhesion of infected red blood cells to brain endothelial cells, and endothelial cell blood-brain barrier disruption.
Topics: Animals; Humans; Bradykinin; Brain; Endothelial Cells; Malaria, Cerebral; Malaria, Falciparum
PubMed: 37637466
DOI: 10.3389/fcimb.2023.1184896 -
Carbohydrate Polymers Nov 2023Pentosan polysulfate sodium (PPS) is a semi-synthetic, heparin-like polysaccharide with manifold therapeutic actions. It is approved for treatment of bladder pain...
Pentosan polysulfate sodium (PPS) is a semi-synthetic, heparin-like polysaccharide with manifold therapeutic actions. It is approved for treatment of bladder pain syndrome / interstitial cystitis in humans and treatment of musculoskeletal diseases in animals. PPS is produced by a complex procedure using beech wood as starting material. It consists of a mixture of sulfated glucuronoxylans, whose structural composition cannot be fully characterized by physicochemical analysis. The question arises whether PPS follow-on products are identical with the original and thus meet the requirement for generic drug application. The aim of this study was to investigate whether commercially available PPS products differ in physicochemical characteristics and biological effects from the original. Ten PPS preparations from different manufactures were analyzed using orthogonal analytical techniques including, inter alia, size exclusion chromatography with triple detection, nuclear magnetic resonance spectroscopy, and high-resolution mid-infrared spectroscopy in aqueous solution with chemometric evaluation. For functional analysis, we measured the plasma kallikrein generation in human plasma and FXII activation. The study revealed significant structural and biological differences between PPS from different sources. Therefore, follow-on products cannot be considered identical but at best similar to original PPS. However, their similar efficacy and safety have still to be proven by comprehensive studies.
PubMed: 37567725
DOI: 10.1016/j.carbpol.2023.121201 -
Clinical and Experimental Immunology Dec 2023C1 inhibitor (C1Inh) is a serine protease inhibitor involved in the kallikrein-kinin system, the complement system, the coagulation system, and the fibrinolytic system....
C1 inhibitor (C1Inh) is a serine protease inhibitor involved in the kallikrein-kinin system, the complement system, the coagulation system, and the fibrinolytic system. In addition to the plasma leakage observed in hereditary angioedema (HAE), C1Inh deficiency may also affect these systems, which are important for thrombosis and inflammation. The aim of this study was to investigate the thromboinflammatory load in C1Inh deficiency. We measured 27 cytokines including interleukins, chemokines, interferons, growth factors, and regulators using multiplex technology. Complement activation (C4d, C3bc, and sC5b-C9/TCC), haemostatic markers (β-thromboglobulin (β-TG), thrombin-antithrombin complexes (TAT), prothrombin fragment 1 + 2 (F1 + 2), active plasminogen activator inhibitor-1 (PAI-1), and the neutrophil activation marker myeloperoxidase (MPO) were measured by enzyme immunoassays. Plasma and serum samples were collected from 20 patients with HAE type 1 or 2 in clinical remission and compared with 20 healthy age- and sex-matched controls. Compared to healthy controls, HAE patients had significantly higher levels of tumour necrosis factor (TNF), interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-7, IL-9, IL-12, and IL-17A, chemokine ligand (CXCL) 8, chemokine ligand (CCL) 3, CCL4, IL-1 receptor antagonist (IL-1RA), granulocyte-macrophage colony-stimulating factor (GM-CSF), fibroblast growth factor (FGF) 2 and platelet-derived growth factor (PDGF)-BB. HAE patients also had higher levels of TAT and F1 + 2. Although granulocyte colony-stimulating factor (G-CSF), β-TG and PAI-1 were higher in HAE patients, the differences did not reach statistical significance after correction for multiple testing. In conclusion, C1Inh deficiency is associated with an increased baseline thromboinflammatory load. These findings may reflect that HAE patients are in a subclinical attack state outside of clinically apparent oedema attacks.
Topics: Humans; Angioedemas, Hereditary; Plasminogen Activator Inhibitor 1; Ligands; Complement C1 Inhibitor Protein; Serpins; Interleukins; Chemokines
PubMed: 37561062
DOI: 10.1093/cei/uxad091 -
The World Allergy Organization Journal Jun 2023Hereditary angioedema (HAE) is a rare, chronic, debilitating genetic disorder characterized by recurrent, unpredictable, and potentially life-threatening episodes of... (Review)
Review
Hereditary angioedema (HAE) is a rare, chronic, debilitating genetic disorder characterized by recurrent, unpredictable, and potentially life-threatening episodes of swelling that typically affect the extremities, face, abdomen, genitals, and larynx. The most frequent cause of HAE is a mutation in the () gene, which either leads to deficient plasma levels of the C1-esterase inhibitor (C1-INH) protein (type I HAE-C1-INH) or normal plasma levels of dysfunctional C1-INH protein (type II HAE-C1-INH). Mutations in are known to be associated with dysregulation of the kallikrein-bradykinin cascade leading to enhancement of bradykinin production and increased vascular permeability. However, some patients present with a third type of HAE (HAE-nl-C1-INH) that is characterized by normal plasma levels and functionality of the C1-INH protein. While mutations in the , , , , , and genes have been identified in some patients with HAE-nI-C1-INH, genetic cause remains unknown in many cases with further research required to fully elucidate the pathology of disease in these patients. Here we review the challenges that arise on the pathway to a confirmed diagnosis of HAE and explore the multifactorial impact of receiving a HAE diagnosis. We conclude that it is important to continue to raise awareness of HAE because delays to diagnosis have a direct impact upon patient suffering and quality of life. Since many patients will seek help from hospitals during their first swelling attack it is vital that emergency department staff are aware of the different pathological pathways that distinguish HAE from other forms of angioedema to ensure that the most appropriate treatment is administered. As disease awareness increases, it is hoped that patients will be diagnosed earlier and that pre-authorization and insurance coverage of HAE treatments will become easier to obtain, ultimately reducing the burden of treatment for these patients and their caregivers.
PubMed: 37448849
DOI: 10.1016/j.waojou.2023.100792 -
Frontiers in Medicine 2023SARS-CoV-2 binds to ACE2 receptors, expressed within the lungs. Risk factors for hospitalization include hypertension, diabetes, ischaemic heart disease and... (Review)
Review
SARS-CoV-2 binds to ACE2 receptors, expressed within the lungs. Risk factors for hospitalization include hypertension, diabetes, ischaemic heart disease and obesity-conditions linked by the presence of endothelial pathology. Viral infection in this setting causes increased conversion of circulating Factor XII to its active form (FXIIa). This is the first step in the contact-kinin pathway, leading to synchronous activation of the intrinsic coagulation cascade and the plasma Kallikrein-Kinin system, resulting in clotting and inflammatory lung disease. Temporal trends are evident from blood results of hospitalized patients. In the first week of symptoms the activated partial thromboplastin time (APTT) is prolonged. This can occur when clotting factors are consumed as part of the contact (intrinsic) pathway. Platelet counts initially fall, reflecting their consumption in coagulation. Lymphopenia occurs after approximately 1 week, reflecting the emergence of a lymphocytic pneumonitis [COVID-19 acute respiratory distress syndrome (ARDS)]. Intrinsic coagulation also induces the contact-kinin pathway of inflammation. A major product of this pathway, bradykinin causes oedema with ground glass opacities (GGO) on imaging in early COVID-19. Bradykinin also causes release of the pleiotrophic cytokine IL-6, which causes lymphocyte recruitment. Thromobosis and lymphocytic pneumonitis are hallmark features of COVID-19 ARDS. In this review we examine the literature with particular reference to the contact-kinin pathway. Measurements of platelets, lymphocytes and APTT should be undertaken in severe infections to stratify for risk of developing ARDS.
PubMed: 37448794
DOI: 10.3389/fmed.2023.1208866 -
Frontiers in Immunology 2023Dysregulated complement activation, increased protein citrullination, and production of autoantibodies against citrullinated proteins are hallmarks of rheumatoid...
BACKGROUND
Dysregulated complement activation, increased protein citrullination, and production of autoantibodies against citrullinated proteins are hallmarks of rheumatoid arthritis (RA). Citrullination is induced by immune cell-derived peptidyl-Arg deiminases (PADs), which are overactivated in the inflamed synovium. We characterized the effect of PAD2- and PAD4-induced citrullination on the ability of the plasma-derived serpin C1-inhibitor (C1-INH) to inhibit complement and contact system activation.
METHODS
Citrullination of the C1-INH was confirmed by ELISA and Western blotting using a biotinylated phenylglyoxal probe. C1-INH-mediated inhibition of complement activation was analyzed by C1-esterase activity assay. Downstream inhibition of complement was studied by C4b deposition on heat-aggregated IgGs by ELISA, using pooled normal human serum as a complement source. Inhibition of the contact system was investigated by chromogenic activity assays for factor XIIa, plasma kallikrein, and factor XIa. In addition, autoantibody reactivity to native and citrullinated C1-INH was measured by ELISA in 101 RA patient samples.
RESULTS
C1-INH was efficiently citrullinated by PAD2 and PAD4. Citrullinated C1-INH was not able to bind the serine protease C1s and inhibit its activity. Citrullination of the C1-INH abrogated its ability to dissociate the C1-complex and thus inhibit complement activation. Consequently, citrullinated C1-INH had a decreased capacity to inhibit C4b deposition the classical and lectin pathways. The inhibitory effect of C1-INH on the contact system components factor XIIa, plasma kallikrein, and factor XIa was also strongly reduced by citrullination. In RA patient samples, autoantibody binding to PAD2- and PAD4-citrullinated C1-INH was detected. Significantly more binding was observed in anti-citrullinated protein antibody (ACPA)-positive than in ACPA-negative samples.
CONCLUSION
Citrullination of the C1-INH by recombinant human PAD2 and PAD4 enzymes impaired its ability to inhibit the complement and contact systems . Citrullination seems to render C1-INH more immunogenic, and citrullinated C1-INH might thus be an additional target of the autoantibody response observed in RA patients.
Topics: Humans; Citrullination; Protein-Arginine Deiminases; Factor XIIa; Plasma Kallikrein; Factor XIa; Arthritis, Rheumatoid; Proteins; Autoantibodies
PubMed: 37426666
DOI: 10.3389/fimmu.2023.1203506 -
The Journal of Allergy and Clinical... Nov 2023Patients with hereditary angioedema experience recurrent, sometimes life-threatening, attacks of edema. It is a rare genetic disorder characterized by genetic and...
BACKGROUND
Patients with hereditary angioedema experience recurrent, sometimes life-threatening, attacks of edema. It is a rare genetic disorder characterized by genetic and clinical heterogenicity. Most cases are caused by genetic variants in the SERPING1 gene leading to plasma deficiency of the encoded protein C1 inhibitor (C1INH). More than 500 different hereditary angioedema-causing variants have been identified in the SERPING1 gene, but the disease mechanisms by which they result in pathologically low C1INH plasma levels remain largely unknown.
OBJECTIVES
The aim was to describe trans-inhibitory effects of full-length or near full-length C1INH encoded by 28 disease-associated SERPING1 variants.
METHODS
HeLa cells were transfected with expression constructs encoding the studied SERPING1 variants. Extensive and comparative studies of C1INH expression, secretion, functionality, and intracellular localization were carried out.
RESULTS
Our findings characterized functional properties of a subset of SERPING1 variants allowing the examined variants to be subdivided into 5 different clusters, each containing variants sharing specific molecular characteristics. For all variants except 2, we found that coexpression of mutant and normal C1INH negatively affected the overall capacity to target proteases. Strikingly, for a subset of variants, intracellular formation of C1INH foci was detectable only in heterozygous configurations enabling simultaneous expression of normal and mutant C1INH.
CONCLUSIONS
We provide a functional classification of SERPING1 gene variants suggesting that different SERPING1 variants drive the pathogenicity through different and in some cases overlapping molecular disease mechanisms. For a subset of gene variants, our data define some types of hereditary angioedema with C1INH deficiency as serpinopathies driven by dominant-negative disease mechanisms.
Topics: Humans; Complement C1 Inhibitor Protein; Angioedemas, Hereditary; HeLa Cells; Endopeptidases; Peptide Hydrolases
PubMed: 37301409
DOI: 10.1016/j.jaci.2023.04.023 -
Frontiers in Physiology 2023Patients with the inherited disorder hereditary angioedema (HAE) suffer from episodes of soft tissue swelling due to excessive bradykinin production. In most cases,... (Review)
Review
Patients with the inherited disorder hereditary angioedema (HAE) suffer from episodes of soft tissue swelling due to excessive bradykinin production. In most cases, dysregulation of the plasma kallikrein-kinin system due to deficiency of plasma C1 inhibitor is the underlying cause. However, at least 10% of HAE patients have normal plasma C1 inhibitor activity levels, indicating their syndrome is the result of other causes. Two mutations in plasma protease zymogens that appear causative for HAE with normal C1 inhibitor activity have been identified in multiple families. Both appear to alter protease activity in a gain-of-function manner. Lysine or arginine substitutions for threonine 309 in factor XII introduces a new protease cleavage site that results in formation of a truncated factor XII protein (Δ-factor XII) that accelerates kallikrein-kinin system activity. A glutamic acid substitution for lysine 311 in the fibrinolytic protein plasminogen creates a consensus binding site for lysine/arginine side chains. The plasmin form of the variant plasminogen cleaves plasma kininogens to release bradykinin directly, bypassing the kallikrein-kinin system. Here we review work on the mechanisms of action of the FXII-Lys/Arg and Plasminogen-Glu variants, and discuss the clinical implications of these mechanisms.
PubMed: 37288434
DOI: 10.3389/fphys.2023.1146834 -
BMC Musculoskeletal Disorders May 2023Patients with rheumatoid arthritis (RA) have shown increased levels of neutrophils generating kallikrein-kinin peptides in blood which are potent mediators of...
OBJECTIVE
Patients with rheumatoid arthritis (RA) have shown increased levels of neutrophils generating kallikrein-kinin peptides in blood which are potent mediators of inflammation. This study investigated the association between the bioregulation of kinin-mediated inflammation with the clinical, quality of life, and imaging characteristics (e.g. ultrasonography) of different arthritides.
METHODS
Patients with osteoarthritis (OA, n = 29), gout (n = 10) and RA (n = 8) were recruited and screened for clinical symptoms, quality of life, and ultrasonographical assessment of arthritis. Blood neutrophils were assessed for the expression of bradykinin receptors (B1R and B2R), kininogens and kallikreins by immunocytochemistry with visualization by bright field microscopy. Levels of plasma biomarkers were measured by ELISA and cytometric bead array.
RESULTS
Quality of life (SF-36 domains and summary scores; including pain; and, HAQ) was similar across OA, gout and RA patients; with the exception of worse physical functioning scores between OA and gout patients. Synovial hypertrophy (on ultrasound) differed between groups (p = 0.001), and the dichotomised Power Doppler (PD) score of greater than or equal to 2 (PD-GE2) was marginally significant (p = 0.09). Plasma IL-8 were highest in patients with gout followed by RA and OA (both, P < 0.05). Patients with RA had higher plasma levels of sTNFR1, IL-1β, IL-12p70, TNF and IL-6, compared to OA and gout patients (all, P < 0.05). Patients with OA had higher expression of K1B and KLK1 on blood neutrophils followed by RA and gout patients (both, P < 0.05). Bodily pain correlated with B1R expression on blood neutrophils (r = 0.334, p = 0.05), and inversely with plasma levels of CRP (r = -0.55), sTNFR1 (r = -0.352) and IL-6 (r = -0.422), all P < 0.05. Expression of B1R on blood neutrophils also correlated with Knee PD (r = 0.403) and PD-GE2 (r = 0.480), both P < 0.05.
CONCLUSIONS
Pain levels and quality of life were similar between patients with OA, RA and gout with knee arthritis. Plasma inflammatory biomarkers and B1R expression on blood neutrophils correlated with pain. Targeting B1R to modulate the kinin-kallikrein system may pose as a new therapeutic target in the treatment of arthritis.
Topics: Humans; Kallikreins; Kinins; Interleukin-6; Quality of Life; Arthritis, Rheumatoid; Osteoarthritis; Gout; Biomarkers; Phenotype; Pain; Synovial Fluid
PubMed: 37202736
DOI: 10.1186/s12891-023-06388-9 -
Allergy, Asthma, and Clinical... May 2023Hereditary angioedema (HAE), which is caused by C1-inhibitor (C1-INH) deficiency or dysfunction, is a rare and potentially life-threatening disease. In patients with...
BACKGROUND
Hereditary angioedema (HAE), which is caused by C1-inhibitor (C1-INH) deficiency or dysfunction, is a rare and potentially life-threatening disease. In patients with HAE, excess production of bradykinin causes acute unpredictable recurrent attacks of angioedema in localized regions, including the larynx and intestines. Given the fact that HAE is an autosomal dominant disease, C1-INH produced in patients with HAE is 50% of that produced in healthy individuals. However, most patients with HAE present plasma C1-INH function of < 25% owing to the chronic consumption of C1-INH by kallikrein-kinin, contact, complement, coagulation, and fibrinolysis cascades. Recently, several therapeutic options have been developed for acute attacks and prophylaxis in the treatment of HAE; however, currently, there is no curative therapy for HAE.
CASE PRESENTATION
Here we report the case of a 48-year-old male patient who presented with a long-standing history of HAE and underwent bone marrow transplantation (BMT) for acute myeloid leukemia (AML) at the age of 39 years and has been in complete remission of AML and HAE thereafter. Notably, after BMT, his C1-INH function gradually increased as follows: < 25%, 29%, 37%, and 45.6%. Since his 20 s, he intermittently presented with an acute attack of HAE once every 3 months from the initial attack. Further, after undergoing BMT, the number of acute attacks decreased to twice within 4 years until the age of 45 years, and subsequently, the patient has been free of acute attacks. C1-INH is mainly synthesized by hepatocytes, but it is known to be partially produced and secreted from peripheral blood monocytes, macrophages, endothelial cells, and fibroblasts. We speculate that the C1-INH function may be increased by extrahepatic production of C1-INH, possibly synthesized by differentiated cells derived from hematopoietic and mesenchymal stem cells after BMT.
CONCLUSIONS
This case report supports efforts to focus on extrahepatic production of C1-INH in the next strategy of new treatment development for HAE.
PubMed: 37194078
DOI: 10.1186/s13223-023-00803-5